1. Field of the Invention
The present invention is directed to a non-invasive device and method for analyzing the concentration of blood components, including oxygen saturation, bilirubin, hemoglobin, glucose, hormones and a variety of drugs.
2. Description of the Prior Art
Analysis of blood components is regularly required in hospitals, emergency rooms, doctors' offices, and in patients' homes (in the case of blood glucose analysis for example), for a variety of diagnostic purposes and to monitor therapy. In most cases, blood is obtained by venipuncture or finger prick, which raises small but important concerns regarding pain and the potential for transmission of infectious disease, such as viral hepatitis and human immunodeficiency virus (HIV) infection. The pain associated with blood drawing often inhibits patient compliance with prescribed blood testing, leading to potentially dangerous consequences of undiagnosed disease. Also, the need for trained technicians to draw and handle blood contributes to the high cost of medical care. Furthermore, blood testing procedures take time, which often delays diagnosis. Finally, for practical reasons, blood testing can be done only at intervals, providing only "snap-snot" data regarding the blood component of interest. Under some circumstances, as for example during the assessment of blood losses due to gastrointestinal hemorrhage or during the assessment of the response to hemodialysis, to the treatment of diabetic ketoacidosis, or to the treatment of acute intoxications, it would be desirable to monitor the concentration of one or more blood components continuously.
Blood tests are often performed in "panels;" that is, a number of tests is run on a single drawn blood sample. However, there are also clinical circumstances in which only a single or a small number of tests are required, or when a single test must be performed repeatedly over time. In such cases, noninvasive tests that do not require blood drawing would be particularly useful.
An example of a currently available noninvasive test is pulse oximetry, which measures the adequacy of saturation of arterial blood hemoglobin with oxygen. Mendelson Y., Pulse Oximetry: Theory and Applications for Noninvasive Monitoring, Clinical Chemistry 38: 1601-7, 1992; Hanning CD, Alexander-Williams J M., Pulse Oximetry: A Practical Review, BMJ 311:367-70, 1995; Severinghaus J W and Kelleher J F., Recent developments in pulse oximetry, Anesthesiology 76:1018-38, 1992; Corenman et al., U.S. Pat. No. 4,934,372; Edgar et al., U.S. Pat. No. 4,714,080; Zelin, U.S. Pat. No. 4,819,752; and Wilber, U.S. Pat. No. 4,407,290. Oximeters have become indispensable for screening patients for life-threatening hypoxemia and for monitoring patient safety during procedures such as surgery and childbirth. Oximeters reliably report the relative arterial oxygen level (percent of the maximum that can be carried by the available hemoglobin), but they cannot measure absolute oxygen content of the blood, because their readings are independent of hemoglobin concentration.
In pulse oximeters, light produced by two light-emitting diodes (LEDs) at approximately 660 nm (red) and 940 nm (infrared) are alternately passed through the subject's finger, toe, or ear (or other well-perfused tissue), and the transmitted light is measured by a rapidly-responding photodetector. The light that is not transmitted to the photodetector is absorbed by the finger or is scattered out of the range of the photodetector. The amount of absorbance depends on tissue density and the amount and character of the blood (venous and arterial) that is present in the light path. At each of the two wavelengths, the resulting time-varying measurement of light intensity for the wavelength, termed "photoplethysmography," is roughly inversely proportional to finger volume, which varies with the arterial pulse.
Changes in absorbance (A) are caused by changes in the amount of blood present in the light path, assumed to be primarily changes in the amount of arterial blood due to the arterial pulse. Because absorbance of oxy-hemoglobin differs for light at the two wavelengths, a ratio of change in absorbance of red to change in absorbance of infrared light can be used to measure oxy-hemoglobin percentage. In practice, transmittance (T=10.sup.-A) is measured from each of the photoplethysmograms, absorbance (A=log 1/T) is calculated, and the change in absorbance with the arterial pulse is calculated for each wavelength studied. The two changing absorbances are then electronically divided, and after inconsistent data points are discarded, the ratios are averaged to yield an average ratio of red/infrared absorbance change. The average ratio is then multiplied by a correction factor, which has been empirically determined for each instrument by comparison with oxy-hemoglobin levels measured by a co-oximeter in arterial blood samples in normal subjects with varying levels of oxyhemoglobin produced as a result of breathing gases with varying fractions of inspired oxygen (FiO.sub.2).
Commercial pulse oximeters used to measure the amount of arterial blood oxygen saturation (SaO.sub.2) are available from the following manufacturers: BCI International, Biochem International, Inc., Criticare Systems, Inc., Datascope Corp., Datex Instrumentation Corp., Gambro Engstrom A. B., Invivo Research, Inc., Kontron Instruments, Life Care International, Inc., MSA, Medical Research Laboratories, Minolta Camera Co., Ltd., Nellcor-Puritan-Bennett, Nippon Colin Co., Ltd., Nonin Medical Systems, Inc., Ohmeda, Inc., Palco Labs, PhysioControl, Respironics, Inc., Sensor Medics Corp., Siemens Medical Systems, Inc., Simed Corp. and Spectramed, Inc.
Pulse oximeters can be controlled with various software packages, including those made by EMG Scientific. Signal processing apparatus, such as that disclosed in U.S. Pat. No. 5,490,505, can be used to process the signals generated by a pulse oximeter.
Prior designs of pulse oximeters used to measure arterial oxygen saturation are well known. For example, U.S. Pat. No. 4,653,498 to New, Jr. et al. (1987) describes a display monitor for use with a pulse oximeter of the type wherein light of two different wavelengths is passed through body tissue, such as a finger, an ear or the scalp, so as to be modulated by the pulsatile component of arterial blood therein and thereby indicates oxygen saturation. Similarly, U.S. Pat. Nos. 4,621,643 (1986), 4,700,708 (1987) and 4,770,179 (1988), all to New, Jr. et al., describe disposable probes for use with pulse oximeters.
U.S. Pat. No. 5,810,723 to the same inventor as the instant application, which will issue on Sep. 22, 1998 from copending application number 08/759,582, is entitled Non-Invasive Carboxyhemoglobin Analyzer. In that patent an apparatus and method is disclosed which allows the non-invasive monitoring of a subject's carboxyhemoglobin level, thereby allowing the detection of possible carbon monoxide poisoning. The subject breathes oxygen to lower his reduced hemoglobin level to approximately 0%, thus allowing the detection and differentiation between oxy- and carboxyhemoglobin by modification of a conventional pulse oximeter.
Noninvasive monitors of bilirubin are also available, especially for following the course of neonatal jaundice. See Linder N, Regev A, Gazit G, Carplus M, Mandelberg A, Tamir I, Reichman B., Noninvasive determination of neonatal hyperbilirubinemia: standardization for variation in skin color; Am J Perinatology 11:223-5,1994. Usually, the absorbance by a body part of light near the peak absorption of bilirubin is monitored. Bilirubinometers are generally calibrated by comparison with measured blood bilirubin in the infant to be monitored. Without such calibration, the varying amounts of tissue and blood in the light path limits the accuracy of the measurements. Thus, at least one blood sample is required.
Examples of other blood tests that are often done alone and/or must be repeated at frequent intervals include: blood hemoglobin or hematocrit measurements for patients with known or suspected anemia, actively hemorrhaging from disease or surgery, and/or undergoing transfusion therapy; glycosylated hemoglobin levels in diabetic patients to assist in assessing adequacy of blood glucose control; blood glucose levels in patients with diabetes or suspected hypoglycemia, for diagnosis of hyper- or hypo-glycemia or for monitoring the effectiveness of insulin or oral hypoglycemic therapy; thyroid hormone levels in persons with hyper- or hypothyroidism; ethanol levels in patients suspected of ethanol intoxication; and a variety of drug and drug metabolite levels (e.g. digoxin, theophylline, dilantin, morphine, benzodiazepines, anabolic steroids) in patients undergoing therapy or suspected of being intoxicated with such drugs.
Noninvasive monitors for glucose, ethanol, and other blood components have been suggested, but have not proven to be feasible, accurate, and/or economically viable. Zeller H, Novak P, Landgraf R, Blood Glucose Measurement By Infrared Spectroscopy, Intl J Artif Org 12:12-35, 1989. Examples include the device described by March in U.S. Pat. No. 3,958,560, which measures glucose in the cornea of the eye by determining the rotation of reflected polarized infrared light. Although it does not require blood drawing, March's technique is cumbersome and uncomfortable for patients and rot suitable for routine monitoring.
The techniques of Hutchinson, U.S. Pat. No. 5,009,230; Dahne et al., U.S. Pat. No. 4,655,225; Mendelson et al., U.S. Pat. No. 5,137,023; Rosenthal et al., U.S. Pat. No. 5,028,787; Schlager et al., U.S. Pat. No. 4,882,492; U.S. Pat. No. 5,638,816, Kiani-Azarbayjary, et al.; and Purdy et al., U.S. Pat. No. 5,360,004 use near infrared light (&lt;2.5 cm wavelength) to assess glucose or other blood components. All suffer from inaccuracies due to the relatively weak absorption bands of glucose in the near infrared spectrum, from overlapping absorption from water, proteins, or other blood components, and especially from varying amounts of blood and tissue in the optical path. Some improve their resolution by using pulsatile flow or displacement of blood as in Dahne et al., and Mendelson et al. to provide a subtractable background, but problems with varying and unknown blood path-length persist.
Braig et al., U.S. Pat. No. 5,313,941 describes a device employing mid-infrared light to measure glucose or ethanol, with synchronization of measurements with the cardiac cycle in order to factor out contributions from components of the finger other than arterial blood. Although the use of systole/diastole comparisons help to limit the interfering influences of tissues other than blood, the accuracy of the described instrument also suffers from its inability to take light path length into account. The instrument is calibrated by comparison with blood samples in volunteer subjects, but subjects with varying finger size and/or varying finger blood volume would yield varying results.
Kiani-Azarbayjany, et al., U.S. Pat. No. 5,638,816, describes a device that produces larger-scale oscillations in tissue blood volume than occur with arterial pulses and analyzes the variations in near infrared absorbances during such oscillations to measure glucose, various species of hemoglobin, and drug concentrations in blood. However, Kiani fails to account for or measure change in light path length. Kiani's device solves the problem of an unknown light path length by normalizing the measurement of the blood constituent of interest, e.g. glucose, (by absorbance at a specific infrared wavelength) against that of water (at another specific infrared wavelength). However, the use of induced pulsations invalidates the use of this device to measure specifically arterial constituents (e.g. oxyhemoglobin) and may well invalidate the measurements of specifically intravascular compounds (e.g. hemoglobin), because the pulsations are likely to cause variations in the light path length through other-than-vascular tissue. This is an especially severe problem when significant amounts of fatty tissue are present. Furthermore, the need to define and produce light at wavelengths that completely or nearly completely separate water from glucose may make the instrument expensive and unwieldy.
The availability of a simple, inexpensive, non-invasive monitoring device for measuring various other blood components would greatly simplify diagnosis, would lead to more rapid analysis of blood component concentrations and avoid the risk and discomfort of invasive methods of measuring such components.
A non-invasive blood component analyzer would likely find a substantial market among hospitals, hospital emergency rooms, community emergency medical services, physician's offices, fire and police departments and the like. An accurate, noninvasive glucose analyzer would find an even greater market for the daily, low-cost, home-based self-monitoring of blood glucose by diabetic patients.